Plasma Phosphorylated-Tau, Neurodegeneration, and Clinical Outcomes-Childcare Supplement

项目摘要 老年痴呆症是一种全球性的健康危机，由于没有疾病而加剧 修改治疗。过去阿尔茨海默病临床试验的失败部分是由于晚期 开始治疗和研究入选筛选不准确。在临床环境中，有许多 衰老中认知能力下降的原因以及治疗和预后取决于潜在的病因。 目前筛选阿尔茨海默病病理学的方法包括脑脊液分析和正电子自旋共振成像。 发射断层扫描，这两种方法都没有广泛使用。对于研究实验室和诊所来说， 开发一种可获得的和准确的阿尔茨海默病病理学早期标志物是必不可少的。最近 高灵敏度单分子阵列技术的技术进步创造了机会， 准确测量血液中磷酸化的tau（p-tau），这是阿尔茨海默病的病理标志。 血浆p-tau已成为主要的血液阿尔茨海默氏症生物标志物，显示出与阿尔茨海默氏症的密切相关性。 阿尔茨海默病病理学的其他标志物，将临床阿尔茨海默病与其他痴呆区分开来 亚型，并准确预测死后阿尔茨海默病的病理。血浆p-tau蛋白显示出巨大的 潜在的，但现有的研究主要集中在建立这种敏感性和特异性， 阿尔茨海默病的生物标志物;其预测更具临床意义的纵向结果的能力 仍然是个问题拟议的研究将在纵向队列研究中检查基线血浆p-tau蛋白 因为它与纵向神经退行性变和9年随访期内的临床结局有关。 选择高度临床相关的结果，包括神经退行性变，基于领域的认知， 主观认知能力下降，以及日常生活活动的功能能力，以最大限度地发挥这一潜力 生物标志物被有意义地整合到临床护理中。拟议中的研究将利用富人 资源的范德比尔特记忆和阿尔茨海默氏症中心，范德比尔特大学成像科学研究所， 和瑞典Sahlovenska大学医院的临床神经化学实验室。这项研究将 由一个跨学科的导师团队指导，包括老年神经心理学，阿尔茨海默氏症， 疾病，磁共振成像，主观认知下降，液体生物标志物，临床管理 异常认知老化，并进行统计分析。平行培训计划将有助于候选人 获得必要的知识和技能，研究血液为基础的阿尔茨海默氏症的生物标志物，并推动他 成为一名成功的独立临床科学家了解血浆的预测有效性 临床相关结果的p-tau将提供进一步研究所需的基本信息。 开发这种生物标志物作为临床试验招募的工具， 阿尔茨海默病和痴呆症的临床护理。

PROJECT SUMMARY Dementia due to Alzheimer’s disease is a global health crisis that is intensified by the absence of disease modifying treatments. The failure of past clinical trials in Alzheimer’s disease has been due in part to late initiation of treatment and inaccurate screening for study inclusion. In clinical settings, there are numerous causes of cognitive decline in aging and treatment and prognosis vary depending on the underlying etiology. Current methods of screening for Alzheimer’s pathology include cerebrospinal fluid analysis and positron emission tomography, both of which are not widely accessible. For both the research lab and the clinic, development of an accessible and accurate early marker of Alzheimer’s pathology is essential. Recent technological advances in highly sensitive single-molecule array techniques have created the opportunity to accurately measure phosphorylated tau (p-tau), a pathological hallmark of Alzheimer’s disease, in the blood. Plasma p-tau has emerged as a leading blood-based Alzheimer’s biomarker, showing strong correlations with other markers of Alzheimer’s pathology, distinguishing clinical Alzheimer’s disease from other dementia subtypes, and accurately predicting post-mortem Alzheimer’s pathology. Plasma p-tau has shown tremendous potential, yet existing research has largely focused on establishing the sensitivity and specificity of this biomarker for Alzheimer’s disease; its ability to predict more clinically meaningful longitudinal outcomes remains in question. The proposed research will examine baseline plasma p-tau in a longitudinal cohort study of aging as it relates to longitudinal neurodegeneration and clinical outcomes over a 9-year follow-up period. Highly clinically relevant outcomes were selected, including neurodegeneration, domain-based cognition, subjective cognitive decline, and functional abilities for activities of daily living, to maximize the potential of this biomarker being meaningfully integrated into clinical care. The proposed research will leverage the rich resources of the Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Institute of Imaging Science, and the Clinical Neurochemistry Laboratory of Sahlgrenska University Hospital, Sweden. The research will be guided by an interdisciplinary mentorship team, including experts in geriatric neuropsychology, Alzheimer’s disease, magnetic resonance imaging, subjective cognitive decline, fluid biomarkers, clinical management of abnormal cognitive aging, and statistical analysis. The parallel training plan will facilitate the candidate’s acquisition of the necessary knowledge and skills to study blood-based Alzheimer’s biomarkers and propel him into a successful career as an independent clinician-scientist. Understanding the predictive validity of plasma p-tau for clinically relevant outcomes would provide essential information that is necessary for the further development of this biomarker as a tool for clinical trial enrollment, accurate observational research in Alzheimer’s disease, and clinical care of dementia.